Emergence of Antimicrobial Resistance

1
Emergence of Antimicrobial Resistance

• Ebbing Lautenbach, MD, MPH
• Assistant Professor of Medicine and Epidemiology
• Associate Hospital Epidemiologist, Hospital of
  the University of Pennsylvania
• Center for Clinical Epidemiology Biostatistics
• University of Pennsylvania School of Medicine

2
Outline

• Recent trends in emerging antibiotic resistance
• Epidemiology of resistance
• Clinical Impact on resistance
• Strategies to curb further emergence of
  resistance

3
Outline

• Recent trends in emerging antibiotic resistance
• Epidemiology of resistance
• Clinical Impact on resistance
• Strategies to curb further emergence of
  resistance

4
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Emergence of Gram - Resistance
FQ-R P. aeruginosa
Ceftaz-R K. pneumoniae
FQ-R E. coli
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New Agents with Expanded in Vitro
Gram-Positive Activity


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New Agents with Expanded Gram Negative Activity
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Trends in Development of New Antibacterials
R2 0.99
Total New Antibacterial Agents
p 0.007 by linear regression New antibacterial
agent ? new molecular entity (NME) with
antimicrobial properties, administered for
systemic infection topical agents,
immunomodulators excluded
Edwards J, ICAAC, 2003
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Potential Reasons for Pharmaceutical Company
Shifts Away From Anti-infective Development

• Shift in demographics of population to elderly
• Need for treatment of chronic diseases
• Antibiotics become auto-obsolete
• Thought leaders advocating conservative use
• Increasing standards for efficacy and safety
  evaluation
• Increasingly complex patients in clinical trials
• Significantly increased costs in clinical trials
• Attractive to develop agents used for life of
  patients

Edwards J, ICAAC, 2003
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Pharmaceutical RD 15 largest by revenue
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Outline

• Recent trends in emerging antibiotic resistance
• Epidemiology of resistance
• Clinical Impact on resistance
• Strategies to curb further emergence of
  resistance

12
Outline

• Recent trends in emerging antibiotic resistance
• Epidemiology of resistance
• 2 examples
• Fluoroquinolone resistance
• Vancomycin-resistant enterococci
• Clinical Impact on resistance
• Strategies to curb further emergence of
  resistance

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Importance of FQ Resistance

• One of the most commonly used antibiotic
  classes1,2
• Most common antibiotic used in nursing homes3

• Broad spectrum
• Oral bioavailability
• Long half-life
• Well tolerated

1. Thomson, J Antimicrob Chemother, 1994 2. Lee,
Am J Infect Control, 1998 3. Steinman, Ann Intern
Med, 2003
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Quinolones

• DNA Gyrase
• Supercoiling
• 4 subunits
• 2 A subunits (gyrA gene)
• 2 B subunits (gyrB gene)
• Topoisomerase IV
• Acts in terminal stages of DNA replication
• Separates newly replicated daughter strands
• 2 subunits
• ParC (GrlA in S. aureus)
• ParE (GrlB in S. aureus)

DNA gyrase (B subunit)
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Trends in FQ Resistance

• Surveillance study
• GN bacilli
• ICUs from 43 states
• 1994 2000
• 35,790 isolates
• Cipro susceptibility decreased from 86 to 76

No difference across teaching vs
non-teaching 500 beds vs
Neuhauser MM, JAMA 2003289885
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FQ Resistance vs FQ Use
PA (r0.976 pNeuhauser MM, JAMA 2003289885
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FQR-EC and FQ Use
Lautenbach, SHEA, 2002
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FQR-EC and the Dow Jones IA
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Risk Factors for Nosocomial FQ Resistance in E.
coli and K. pneumoniae

• Case-control study (1/1/98 6/30/99)
• Sites
• Hospital of the Univ. of Penn (HUP)
• Presbyterian Medical Center (PMC)
• Subjects identified through Clinical Micro Lab at
  HUP
• Study subjects
• 123 cases (FQ-resistant)
• 70 controls (FQ-susceptible)
• Review of inpatient medical records

Lautenbach, Arch Intern Med 20021622469
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Multivariable Model
Lautenbach, Arch Intern Med 20021622469
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Outline

• Recent trends in emerging antibiotic resistance
• Epidemiology of resistance
• 2 examples
• Fluoroquinolone resistance
• Vancomycin-resistant enterococci
• Clinical Impact on resistance
• Strategies to curb further emergence of
  resistance

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Importance of Enterococci

• 3rd most common hospital pathogen
• 10-12 of all nosocomial infections
• 3rd most common cause of BSI
• 3-4 per 10,000 discharges
• 1980s incidence of enterococcal bacteremia in
  teaching hospitals increased up to 197 1
• 1. NNIS, Am J Med 199191(suppl 3B)86S

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Emergence of VRE

• First isolated in vitro in 1969 1
• Described clinically in 1988 2,3
• Mechanism of resistance
• Alteration of cell wall precursors
• Several resistance phenotypes
• VanA and VanB most clinically significant
• 1. Toala, Am J Med Sci 1969258416 2.
  Leclercq, NEJM 1988319157 3. Uttley,
  Lancet 1988157

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Progression of Vancomycin Resistance Enterococci
Martone WJ. Infect Control Hosp Epidemiol.
199819539-545. NNIS Antimicrobial Resistance
Surveillance Report. 1999. (www.cdCgov/ncidod/hip/
NNIS/AR_Surv1198.htm).
through June 1999
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Risk Factors An Exhaustive (ing) List

• Age
• Duration of hospitalization
• ICU admission
• Renal insufficiency
• Immunosuppression
• Neutropenia
• Hematologic malignancy
• Solid organ transplant
• Bone marrow transplant
• AIDS
• Prior Surgery

• Antibiotics - General
• Number / Duration
• Antibiotics - Specific
• Almost all implicated
• Diarrhea / C. difficile
• Central venous catheter
• Urinary catheter
• Prior Colonization
• Exposure to VRE source
• VRE-infected patient
• Inanimate Object
• Health Care Worker

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Risk factors for VRE (HUP)

• Case control study (1/1/93 - 12/31/95) HUP
• 260 cases enterococcal bacteremia
• 72 VRE
• Risk factor OR (95CI) p value
• Vancomycin use 3.0 (1.4,6.4) .005
• Renal insufficiency 4.4 (2.0,9.7)
• Neutropenia 6.3 (1.5,26.7) .013

Lautenbach, Infect Control Hosp Epidemiol,
199920318
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VRE Risk Factors
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Risk Factors Modifiable Variables

• Age
• Duration of hospitalization
• ICU admission
• Renal insufficiency
• Immunosuppression
• Neutropenia
• Hematologic malignancy
• Solid organ transplant
• Bone marrow transplant
• AIDS
• Prior Surgery

• Antibiotics - General
• Number / Duration
• Antibiotics - Specific
• Almost all implicated
• Diarrhea / C. difficile
• Central venous catheter
• Urinary catheter
• Prior Colonization
• Exposure to VRE source
• VRE-infected patient
• Inanimate Object
• Health Care Worker

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Exposure to VRE Source

• To develop VRE infection, one must first be
  exposed to the organism
• Extent of exposure is related to other risk
  factors
• Duration of hospitalization
• ICU admission
• Age
• Greater severity of illness
• Indwelling devices

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Sources of VRE Acquisition

• VRE-infected patients
• Colonization pressure 1
• Inanimate objects
• Gowns, Bed linens, Cabinets, ECG wires, Floors,
  etc.
• Room contamination
• 50 of rooms may become contaminated
• May remain viable up to several months
• Healthcare workers?
• 1. Bonten, Arch Intern Med 19981581127

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Outline

• Recent trends in emerging antibiotic resistance
• Epidemiology of resistance
• Clinical impact on resistance
• Strategies to curb further emergence of
  resistance

32
Impact of Antimicrobial Resistance

• Increased morbidity / mortality 1,2
• Increased cost
• Estimated annual excess hospital costs in the
  United States 100 million - 30 billion3

1. Patton, Med Clin North Am, 1991 2. Cohen,
Science, 1992 3. Phelps, Med Care, 1989
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Impact of Resistance on Antibiotic Use

• Increased complexity of empiric antibiotic
  coverage
• Greater empiric use of antibiotics
• Increased use of broad spectrum antibiotics
• Perpetuates the cycle of resistance

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Impact of FQ Resistance on Clinical Outcome

• Retrospective cohort design
• All patients with clinical E. coli or K.
  pneumoniae isolates
• 123 patients with FQ-resistant isolate
• 70 patients with FQ-susceptible isolate
• January 1, 1998 - June 30, 1999
• Sites
• Hospital of the Univ. of Penn (HUP)
• 725-bed academic medical center
• Presbyterian Medical Center (PMC)
• 344-bed urban community hospital

Lautenbach et al, SHEA, 2002
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Results Mortality
P0.05
Lautenbach, SHEA, 2002
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Multivariable Model Risk Factors for Mortality
Lautenbach, SHEA, 2002
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Time to Effective Therapy
Lautenbach et al, SHEA, 2002
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Impact of VRE on Emergence of Other Resistance
Patterns

• Resistance transferable to S. aureus in vitro 1
• 8-month prospective study of S. aureus and VRE
  co-colonization in the GI tract 2
• Of 37 patients colonized with VRE, 23 (62) had
  S. aureus recovered from stool
• Of these, 20 (87) had MRSA
• 25 of stools with S. aureus contained 1,000,000
  organisms/gram of stool

1. Noble WC, FEMS Microbiol Lett 1992 72195 2.
Ray AJ, Clin Infect Dis 2003 37875
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Glycopeptide Resistance in S. aureus
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VISA Isolates PFGE Analysis
Lane 1-S. Aureus Lane 2-MRSA Lane 3-VISA
(pt1) Lane 4-MRSA (pt1) Lane 5-VISA (pt2)
Smith, NEJM 1999340493
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VRSA - 2002
VanA
Chang S, N Engl J Med 20033481342
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Outline

• Recent trends in emerging antibiotic resistance
• Epidemiology of resistance
• Clinical impact on resistance
• Strategies to curb further emergence of
  resistance

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Prevention of Spread VRE

• How do findings relate to infection risk?
• Only a minority of patients become colonized when
  cared for in a contaminated room 1
• Elucidation of mechanisms of VRE acquisition
• Implement more effective infection control
  interventions
• Enhanced surveillance
• Patients infected or colonized with VRE have
  equal potential for transmission
• Patient transfer between facilities
• 1. Bonten, Lancet 19963481615

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Antibiotic Use Is There Room for Improvement?
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• The desire to ingest medicines is one of the
  principal features which distinguish man from the
  animals
• Osler W. Aecquanimitas,1920

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Implications Addressing FQ Overuse / Misuse

• On whom/Where are they being used?
• Inpatient
• Outpatient
• Emergency Departments
• Why/How are they being used?
• Indications
• Dose/duration

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How are FQs Used Appropriateness in Inpatients
Ena, Diagn Microbiol Infect Dis 1998
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Appropriateness of FQ Use EDs

• FQ Drug Use Evaluation (DUE)
• Sites 2 Academic Medical Center Emergency
  Departments (EDs)
• Subjects 100 patients seen in EDs, then
  discharged
• Appropriateness (of indication) of therapy judged
  by existing institutional guidelines
• www.med.upenn.edu/bugdrug
• 3 independent ID reviewers

Lautenbach, Arch Intern Med 2003163601
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Appropriateness of ED FQ Use
81 of courses inappropriate
Lautenbach, Arch Intern Med 2003163601
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Appropriateness by Site of Infection
p0.76
Lautenbach, Arch Intern Med 2003163601
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Appropriateness of FQ Use EDs

• 19/100 (19) patients received appropriate FQ
  therapy (judged by indication)
• 14 received both an incorrect dose duration
• 4 received either an incorrect dose or duration
• 1 received the correct dose and duration
• Variation of FQ use by ED
• ED1 (training program) 74 inappropriate
• ED2 (no training program) 86 inappropriate
• OR (95CI) 0.39 (0.14, 1.09)

Lautenbach, Arch Intern Med 2003163601
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Potential Strategies

• Guidelines
• Antibiotic cycling
• Antimicrobial optimization

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Potential Strategies

• Guidelines
• Antibiotic cycling
• Antimicrobial optimization

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Awareness and Use of CAP Guidelines

• Survey study of 621 physicians
• ATS CAP guidelines / local CAP guidelines
• 7 Pittsburgh area hospitals
• 1 University
• 3 community teaching
• 3 community non-teaching
• 345/621 (56) responded
• Generalists (79)
• ID (6)
• Pulmonologist (5)

Switzer GE, J Gen Intern Med 200318816
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Awareness and Use of CAP Guidelines
n345
Switzer GE, J Gen Intern Med 200318816
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Predictors of Use of ATS Guidelines
Goldberg Personality Scale
Switzer GE, J Gen Intern Med 200318816
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Awareness and Use of CAP Guidelines

• 6 of 7 study hospitals had local guidelines for
  CAP
• 290 respondents from the 6 hospitals
• 41 reported that no local guidelines existed
• 30 of respondents reported they used the
  guideline more than half of the time in CAP
  therapy
• 48 respondents from the hospital without a
  guideline,
• 14 said it their hospital did have a guideline
• Local CAP guideline use was associated with
• Practicing as a generalist OR0.10 95CI
  (0.01-0.89)
• Positive attitude toward guidelines OR1.05
  95CI (0.99-1.11)

Switzer GE, J Gen Intern Med 200318816
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Limitations of Guidelines

• Discrepancies across guidelines
• Lack of RCT data to support recommendations
• Little regional/local susceptibility data
• Poor correlation between in vitro resistance and
  clinical response
• Failure to consider future emergence of resistance

Luh JY, Arch Intern Med 20031631617
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Potential Strategies

• Guidelines
• Antibiotic cycling
• Antimicrobial optimization

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Antibiotic Cycling

• Periodic removal of certain agents / classes
• Goals
• Prevention of VAP
• Curb emergence of antibiotic resistance
• Optimize empiric antibiotic selection
• Assumptions
• Resistance emerges through selective pressure
• Strict antibiotic control
• Closed population
• No patient to patient transmission
• No co-selection of resistance

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Antibiotic Cycling

• Prospective cohort study conducted in ICU
• University of Virginia
• General, trauma, or transplant surgery patients
• 2 year study
• 1 year non-protocol driven antibiotic use
• 1 year of rotating empirical antibiotic
  assignment
• November 1997 October 1999

Raymond DP, Crit Care Med 2001291101
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Antibiotic Cycling
a - add clindamycin for pneumonia if aspiration
suspected b imipenem or meropenem
c- add
ampicillin or vancomycin if Enterococcus is
suspected
Raymond DP, Crit Care Med 2001291101
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Antibiotic Cycling

• Variable Year 1 Year 2 p value
• Resistant GPC Infections 14.6 7.8
• Resistant GNB Infections 7.7 2.5
• Infection-related mortality 9.6 2.9
• Liver disease 19 (10.8) 8 (5.6)
• Transplantation 27 (15.3) 6 (4.2) 0.001
• All variables per 100 admissions
• Limitations
• Concurrent ceftazidime to cefepime formulary
  switch
• Concurrent infection control interventions

Raymond DP, Crit Care Med 2001291101
64
Potential Strategies

• Guidelines
• Antibiotic cycling
• Antimicrobial optimization

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Antimicrobial Optimization

• Decrease unnecessary antibiotic use
• Develop / apply guidelines for antibiotic use
• Tailor empiric antibiotic selection to particular
  situation
• Patient specific
• Maintain broad choice of agents
• Several approaches
• Human
• Computer

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Antimicrobial Optimization

• Decrease unnecessary antibiotic use
• Develop / apply guidelines for antibiotic use
• Tailor empiric antibiotic selection to particular
  situation
• Patient specific
• Maintain broad choice of agents
• Several approaches
• Human
• Computer

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Antibiotic Management Programs

• University of Pennsylvania
• 1993 - Antibiotic management program (AMP)
• Formulary redesigned
• Guidelines developed
• AMT team
• Approval of restricted agents
• Streamlining of therapy

Gross R, Clin Infect Dis 200133289
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Antibiotic Management Programs
Gross R, Clin Infect Dis 200133289
69
Antimicrobial Optimization

• Decrease unnecessary antibiotic use
• Develop / apply guidelines for antibiotic use
• Tailor empiric antibiotic selection to particular
  situation
• Patient specific
• Maintain broad choice of agents
• Several approaches
• Human
• Computer

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Computer Support
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Computer Decision Support

• Prospective before-after study of a computerized
  anti-infectives management program
• 12-bed ICU
• LDS Hospital, Salt Lake City
• June 1992 June 1995
• 2 year before period
• 1 year after period

Evans RS, NEJM 1998338232
72
Computer Decision Support

• Computer system
• Data incorporated
• Patient information admission diagnosis, WBC
  count, temperature, surgical data, chest
  radiograph, microbiology data, pathology data,
  serologic data, allergies, past infection
• Institution information 5-year antibiogram
• Output
• Suggest antibiotic regimen that would cover the
  identified and potential pathogens

Evans RS, NEJM 1998338232
73
Computer Decision Support

• Variable Before (n766) After (n203) p value
• different abx ordered 2.0 (1.9, 2.1) 1.5 (1.3,
  1.7)
• Duration of abx (hrs) 214 (177-251) 103
  (45-160)
• abx doses 23.6 (20.326.9) 11.4
  (6.2-16.7)
• ICU Length of stay (ds) 4.9 (4.1-5.8) 2.7
  (1.5-4.0)
• Total Length of stay 12.9 (11.5-14.4) 10.0
  (7.7-12.3)
• Total hospital cost 35K (31K-39K) 26K
  (20K-32K)
• Includes only those patients for whom computer
  regimen was followed
• Values are means per patient and 95CIs

Evans RS, NEJM 1998338232
74
Trends in Antimicrobial Prescribing

• Cross sectional survey
• National Ambulatory Medical Care Survey (NCAMS)
• Overall abx use
• Adults 13 10 (p
• Peds 33 22 (p
• Broad Spectrum abx use
• Adults 24 48 (p
• Peds 23 40 (p

Steinman MA, Ann Intern Med 2003138525
75
Trends in Antimicrobial Prescribing
Steinman MA, Ann Intern Med 2003138525
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Conclusions

• Antimicrobial resistance increasing
• Negative impact of resistance on clinical
  outcomes
• Many potential interventions
• All require more study
• Judicious use of current agents critical to
  preserve future use

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Emergence of Antimicrobial Resistance

• Ebbing Lautenbach, MD, MPH
• Assistant Professor of Medicine and Epidemiology
• Associate Hospital Epidemiologist, Hospital of
  the University of Pennsylvania
• Center for Clinical Epidemiology Biostatistics
• University of Pennsylvania School of Medicine